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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Muscular dystrophy is a group of genetically determined muscular disorders marked by progressive wasting and weakness of the skeletal muscle, but which often affect cardiac and smooth muscles or other tissues. The patterns of inheritance are either dominant or recessive although the gene may be defective because of a new mutation. Growing evidence revealed the marked heterogeneity of the muscle disorders, and considerable numbers of Japanese scientists and physicians have contributed to the research progress in muscular dystrophy. Among these the discovery of an increased serum creatine kinase activity in muscular dystrophy opened the way for the most reliable laboratory test for muscular dystrophy in 1959, and subsequently accelerated progress in a broad range of research areas in medicine. Progress in modern genetics and molecular pathology provided another breakthrough in muscular dystrophy research and, in 1987, dystrophin was identified, a deficiency of which causes DMD. The present review article highlights contributions of Japanese scientists to muscular dystrophy research.
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PMID:Muscular dystrophy. 1103 85

Muscular dystrophies (MD) are a clinically and genetically heterogeneous group of skeletal muscle-wasting diseases. Mutations in the dystrophin gene result in dystrophin deficiency, which constitutes the pathogenic basis of Duchenne and Becker MD (DMD and BMD). Several MD are caused by mutations in other recently identified genes coding for proteins linked to the sarcolemma, the nuclear envelope or the contractile apparatus. In addition, several MD have been mapped to different chromosomal loci and for most of them, the identification of the molecular defect is underway. The immediate result is an ongoing reclassification of the MD into disorders defined not by clinical characteristics but specific genetic mutations. At present, therapy of MD is based on symptomatic treatment and supportive care. Convincing evidence for clinical efficacy is only available for corticosteroids that also suffer from frequent and severe side effects. Up to now, curative therapy is not available, although promising new molecular therapies are under investigation in animal models of MD. Current treatment strategies are discussed and a perspective for effective molecular therapy is given.
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PMID:Novel approaches to treat muscular dystrophies. 1128 19

Muscular dystrophy is a nosology for a group of hereditary muscle disorders characterized by progressive wasting and weakness of skeletal muscle, where degeneration of muscle fibers is detected by pathological examination. Since the causative gene of Duchenne muscular dystrophy (DMD), the most severe and abundant form of muscular dystrophy, the DMD gene, and its product dystrophin was isolated by positional cloning by Dr. Kunkel and his colleagues, the studies on molecular pathologies of muscular dystrophy has been extensively developed. The current therapeutic approaches of muscular dystrophy, such as DMD involves pharmacological suppression of the inflammatory and immure responses, which usually provides only modest and temporary beneficial effects. Future approaches depend on cell and gene therapy technology and will require different strategies, none of which are currently ready to enter clinical practice. These approaches involve the efficient, non-antigenic gene transfer for in vivo gene therapy, pharmacological upregulation of the synthesis of utrophin, a related protein that compensates for the loss of dystrophin, and myogenic stem cell transplantation. These approaches could be integrated each other and called as molecular therapy.
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PMID:[Molecular therapy of muscular dystrophy]. 1146 75

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and alpha-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.
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PMID:Function and genetics of dystrophin and dystrophin-related proteins in muscle. 1191 91

Duchenne muscular dystrophy is a debilitating muscle-wasting disease caused by mutations in the dystrophin gene - one of the largest genes identified thus far - and which ultimately results in premature death. With no current treatment available, the hopes of many sufferers lie in the establishment of an effective gene therapy. The adeno-associated virus is now emerging as a premium gene transfer vector eliciting minimal immune response from the host and allowing for long-term gene expression. It is the scope of this review to examine the recent efforts that have been made to develop ultra-truncated versions of the dystrophin gene that retain functionality, yet can still be cloned into recombinant adeno-associated viral vectors and other low-capacity vector systems.
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PMID:The future of Duchenne muscular dystrophy gene therapy: shrinking the dystrophin gene. 1222 72

Duchenne muscular dystrophy (DMD) is a severe progressive muscle-wasting disorder caused by mutations in the dystrophin gene. Studies have shown that bone marrow cells transplanted into lethally irradiated mdx mice, the mouse model of DMD, can become part of skeletal muscle myofibers. Whether human marrow cells also have this ability is unknown. Here we report the analysis of muscle biopsies from a DMD patient (DMD-BMT1) who received bone marrow transplantation at age 1 year for X-linked severe combined immune deficiency and who was diagnosed with DMD at age 12 years. Analysis of muscle biopsies from DMD-BMT1 revealed the presence of donor nuclei within a small number of muscle myofibers (0.5-0.9%). The majority of the myofibers produce a truncated, in-frame isoform of dystrophin lacking exons 44 and 45 (not wild-type). The presence of bone marrow-derived donor nuclei in the muscle of this patient documents the ability of exogenous human bone marrow cells to fuse into skeletal muscle and persist up to 13 years after transplantation.
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PMID:Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation. 1223 12

Patients with Duchenne muscular dystrophy (DMD), an X-linked lethal muscle-wasting disease, have abnormal expression of the protein dystrophin within their muscle fibres. In the mdx mouse model of this condition, both germline and neonatal somatic gene transfers of dystrophin cDNAs have demonstrated the potential of gene therapy in treating DMD. However, in many DMD patients, there appears to be no dystrophin expression when muscle biopsies are immunostained or western blots are performed. This raises the possibility that the expression of dystrophin following gene transfer might trigger a destructive immune response against this 'neoantigen'. Immune responses can also be generated against the gene transfer vector used to transfect the dystrophic muscle, and the combined immune response could further damage the already inflamed muscle. These problems are now beginning to be investigated in immunocompetent mdx mice. Although much work remains to be done, there are promising indications that these immune responses might not prove as much of a concern as originally envisaged.
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PMID:Immunological hurdles in the path to gene therapy for Duchenne muscular dystrophy. 1458 59

Duchenne muscular dystrophy is an X-linked recessive disorder, primarily characterized by progressive muscle weakness and wasting. The disease results from the absence of dystrophin, however the precise molecular mechanisms leading to muscle pathology are poorly understood. Dystrophic muscles undergo increased oxidative stress and altered calcium homeostasis, which may contribute to myofiber loss by triggering both necrosis and apoptosis. Recent studies have identified ARC (apoptosis repressor with caspase recruitment domain) as an abundant protein in human muscle that can inhibit both hypoxia and caspase-8-induced apoptosis as well as protect cells from oxidative stress. To explore a potential role for ARC in protecting muscle fibers from dystrophic breakdown, we have cloned and characterized murine ARC and studied its expression in normal and dystrophic mouse muscle. ARC is expressed at high levels in striated muscle and displays fiber-type restricted expression patterns. ARC expression levels are normal in dystrophic mdx mice, although the intracellular localization pattern of ARC is slightly altered compared with normal muscles. Overexpression of ARC in transgenic mdx mice failed to alleviate the dystrophic pathology in skeletal muscles, suggesting that misregulation of the molecular pathways regulated by ARC does not significantly contribute to myofiber death.
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PMID:Characterization of ARC, apoptosis repressor interacting with CARD, in normal and dystrophin-deficient skeletal muscle. 1464 4

1. Duchenne muscular dystrophy (DMD) is a severe disease of skeletal muscle, characterized by an X-linked recessive inheritance and a lack of dystrophin in muscle fibres. It is associated with progressive and severe wasting and weakness of nearly all muscles and premature death by cardiorespiratory failure. 2. Studies investigating the susceptibility of dystrophic skeletal muscles to contraction-mediated damage, especially after lengthening actions where activated muscles are stretched forcibly, have concluded that dystrophin may confer protection to muscle fibres by providing a mechanical link between the contractile apparatus and the plasma membrane. In the absence of dystrophin, there is disruption to normal force transmission and greater stress placed upon myofibrillar and membrane proteins, leading to muscle damage. 3. Contraction protocols (involving activation and stretch of isolated muscles or muscle fibres) have been developed to assess the relative susceptibility of dystrophic (and otherwise healthy) muscles to contraction-induced injury. These protocols have been used successfully to determine the relative efficacy of different (gene, cell or pharmacological) interventions designed to ameliorate or cure the dystrophic pathology. More research is needed to develop specific 'contraction assays' that will assist in the evaluation of the clinical significance of different therapeutic strategies for muscular dystrophy.
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PMID:Role of contraction-induced injury in the mechanisms of muscle damage in muscular dystrophy. 1529 51

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease due to a mutation in the dystrophin gene and the consequential protein deficiency in muscle. How the lack of the sarcolemmal protein dystrophin gives rise to the final disease status is still not clear. Several evidences suggest a role of nuclear factor kappa-B (NF-kappaB), a pleiotropic transcription factor, in muscle degeneration and regeneration in DMD patients and mdx mice. We investigated the effects of NF-kappaB blocking by pyrrolidine dithiocarbamate (PDTC), a well-known NF-kappaB inhibitor, on dystrophic process in mdx mice. Five-week-old mdx and wild-type mice received three times a week for 5 weeks either PDTC (50 mg/kg) or its vehicle. PDTC treatment: (i) increased forelimb strength (+20%; P < 0.05) and strength normalized to weight (+24%; P < 0.05) and a decreased fatigue percentage (-61%; P < 0.05) in mdx mice, (ii) blunted the augmented NF-kappaB nuclear binding activity and the enhanced TNF-alpha expression in dystrophic muscles (P < 0.01), (iii) at a quantitative morphological evaluation of extensor digitorum longus (EDL) and biceps muscles, increased area with normal fibers (P < 0.05, in EDL), reduced muscle necrosis (P < 0.05 in biceps; P < 0.01 in EDL), and enhanced muscle regeneration (P < 0.01, in biceps). Our data support the hypothesis that NF-kappaB contributes to the perpetuation of the dystrophic damage and show that its blockade produces beneficial effects on functional, biochemical, and morphological parameters in mdx mice. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD.
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PMID:Nuclear factor kappa-B blockade reduces skeletal muscle degeneration and enhances muscle function in Mdx mice. 1641 3


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